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1.
Trends Immunol ; 40(1): 1-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503793

RESUMO

Memory was traditionally considered an exclusive hallmark of adaptive immunity. This dogma was challenged by recent reports that myeloid cells can retain 'memory' of earlier challenges, enabling them to respond strongly to a secondary stimulus. This process, designated 'trained immunity', is initiated by modulation of precursors of myeloid cells in the bone marrow. The ancestral innate immune system of lower organisms (e.g., Caenorhabditis elegans) can build long-lasting memory that modifies responses to secondary pathogen encounters. We posit that changes in cellular metabolism may be a common denominator of innate immune memory from lower animals to mammals. We discuss evidence from C. elegans and murine/human systems supporting the concept of an ancestral principle regulating innate immune memory by controlling cellular metabolism.


Assuntos
Caenorhabditis elegans/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Animais , Humanos
2.
BMC Biol ; 18(1): 31, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188449

RESUMO

BACKGROUND: Metabolic activity alternates between high and low states during different stages of an organism's life cycle. During the transition from growth to quiescence, a major metabolic shift often occurs from oxidative phosphorylation to glycolysis and gluconeogenesis. We use the entry of Caenorhabditis elegans into the dauer larval stage, a developmentally arrested stage formed in response to harsh environmental conditions, as a model to study the global metabolic changes and underlying molecular mechanisms associated with growth to quiescence transition. RESULTS: Here, we show that the metabolic switch involves the concerted activity of several regulatory pathways. Whereas the steroid hormone receptor DAF-12 controls dauer morphogenesis, the insulin pathway maintains low energy expenditure through DAF-16/FoxO, which also requires AAK-2/AMPKα. DAF-12 and AAK-2 separately promote a shift in the molar ratios between competing enzymes at two key branch points within the central carbon metabolic pathway diverting carbon atoms from the TCA cycle and directing them to gluconeogenesis. When both AAK-2 and DAF-12 are suppressed, the TCA cycle is active and the developmental arrest is bypassed. CONCLUSIONS: The metabolic status of each developmental stage is defined by stoichiometric ratios within the constellation of metabolic enzymes driving metabolic flux and controls the transition between growth and quiescence.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Diapausa/genética , Regulação da Expressão Gênica no Desenvolvimento , Transdução de Sinais/genética , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo
3.
Nat Chem Biol ; 13(6): 647-654, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28369040

RESUMO

The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF-ß mutant worms caused by impaired intracellular sterol trafficking. PEGC biosynthesis depends on functional NPC1 and TGF-ß, indicating that these proteins control larval development at least partly through PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts. However, the resulting developmental arrest could be rescued by oversaturation of food with cholesterol. Taken together, these data show that PEGC is essential for C. elegans development through its regulation of sterol mobilization.


Assuntos
Caenorhabditis elegans/metabolismo , Colesterol/metabolismo , Glicoesfingolipídeos/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Cromatografia Líquida , Espectrometria de Massas , Estrutura Molecular , Mutação , Fosforilação
4.
Nat Chem Biol ; 10(4): 281-5, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24584102

RESUMO

Survival of nematode species depends on how successfully they disperse in the habitat and find a new host. As a new strategy for collective host finding in the nematode Pristionchus pacificus, dauer larvae synthesize an extremely long-chain polyunsaturated wax ester (nematoil) that covers the surface of the animal. The oily coat promotes congregation of up to one thousand individuals into stable 'dauer towers' that can reach a beetle host more easily.


Assuntos
Interações Hospedeiro-Parasita/fisiologia , Nematoides/fisiologia , Ceras , Animais , Evolução Biológica , Besouros/parasitologia , Ecossistema , Ésteres , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Larva , Metabolismo dos Lipídeos/fisiologia , Lipídeos/química
5.
Anal Chem ; 86(5): 2703-10, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24471557

RESUMO

A commonly accepted LIPID MAPS classification recognizes eight major lipid categories and over 550 classes, while new lipid classes are still being discovered by targeted biochemical approaches. Despite their compositional diversity, complex lipids such as glycerolipids, glycerophospholipids, saccharolipids, etc. are constructed from unique structural moieties, e.g., glycerol, fatty acids, choline, phosphate, and trehalose, that are linked by amide, ether, ester, or glycosidic bonds. This modular organization is also reflected in their MS/MS fragmentation pathways, such that common building blocks in different lipid classes tend to generate common fragments. We take advantage of this stereotyped fragmentation to systematically screen for new lipids sharing distant structural similarity to known lipid classes and have developed a discovery approach based on the computational querying of shotgun mass spectra by LipidXplorer software. We applied this concept for screening lipid extracts of C. elegans larvae at the dauer and L3 stages that represent alternative developmental programs executed in response to environmental challenges. The search, covering more than 1.5 million putative chemical compositions, identified a novel class of lyso-maradolipids specifically enriched in dauer larvae.


Assuntos
Lipídeos/química , Animais , Caenorhabditis elegans/metabolismo , Espectrometria de Massas em Tandem
6.
Artigo em Inglês | MEDLINE | ID: mdl-38253416

RESUMO

Lipids are characterized by extremely high structural diversity translated into a wide range of physicochemical properties. As such, lipids are vital for many different functions including organization of cellular and organelle membranes, control of cellular and organismal energy metabolism, as well as mediating multiple signaling pathways. To maintain the lipid chemical diversity and to achieve rapid lipid remodeling required for the responsiveness and adaptability of cellular membranes, living systems make use of a network of chemical modifications of already existing lipids that complement the rather slow biosynthetic pathways. Similarly to biopolymers, which can be modified epigenetically and posttranscriptionally (for nucleic acids) or posttranslationally (for proteins), lipids can also undergo chemical alterations through oxygenation, nitration, phosphorylation, glycosylation, etc. In this way, an expanded collective of modified lipids that we term the "epilipidome," provides the ultimate level of complexity to biological membranes and delivers a battery of active small-molecule compounds for numerous regulatory processes. As many lipid modifications are tightly controlled and often occur in response to extra- and intracellular stimuli at defined locations, the emergence of the epilipidome greatly contributes to the spatial and temporal compartmentalization of diverse cellular processes. Accordingly, epilipid modifications are observed in all living organisms and are among the most consistent prerequisites for complex life.


Assuntos
Membrana Celular , Lipídeos de Membrana , Membrana Celular/metabolismo , Lipídeos de Membrana/metabolismo , Humanos , Animais , Metabolismo dos Lipídeos , Transdução de Sinais
7.
Commun Biol ; 7(1): 121, 2024 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-38267699

RESUMO

Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. Here we show that cholesterol bound to the small secreted proteins SCL-12 or SCL-13 is sequestered in the gut lumen during the dauer state. Upon recovery from dauer, bound cholesterol undergoes endocytosis into lysosomes of intestinal cells, where SCL-12 and SCL-13 are degraded and cholesterol is released. Free cholesterol activates mTORC1 and is used for the production of dafachronic acids. This leads to promotion of protein synthesis and growth, and a metabolic switch at the transcriptional level. Thus, mobilization of sequestered cholesterol stores is the key event for transition from quiescence to growth, and cholesterol is the major signaling molecule in this process.


Assuntos
Caenorhabditis elegans , Esteroides , Animais , Caenorhabditis elegans/genética , Colesterol , Alvo Mecanístico do Complexo 1 de Rapamicina , Hormônios
8.
Front Aging ; 4: 1031161, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37731965

RESUMO

The dauer larva is a specialized stage of worm development optimized for survival under harsh conditions that have been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of Caenorhabditis elegans may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of a dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggested that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how feeding frequency and amplitude affect lifespan extension. Based on the comparison of the model with experimental data for fixed ethanol concentration, we proposed the range of feeding protocols that could lead to even longer dauer survival and it can be tested experimentally.

9.
Nat Commun ; 12(1): 2321, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875652

RESUMO

Bactericidal antibiotics kill bacteria by perturbing various cellular targets and processes. Disruption of the primary antibiotic-binding partner induces a cascade of molecular events, leading to overproduction of reactive metabolic by-products. It remains unclear, however, how these molecular events contribute to bacterial cell death. Here, we take a single-cell physical biology approach to probe antibiotic function. We show that aminoglycosides and fluoroquinolones induce cytoplasmic condensation through membrane damage and subsequent outflow of cytoplasmic contents as part of their lethality. A quantitative model of membrane damage and cytoplasmic leakage indicates that a small number of nanometer-scale membrane defects in a single bacterium can give rise to the cellular-scale phenotype of cytoplasmic condensation. Furthermore, cytoplasmic condensation is associated with the accumulation of reactive metabolic by-products and lipid peroxidation, and pretreatment of cells with the antioxidant glutathione attenuates cytoplasmic condensation and cell death. Our work expands our understanding of the downstream molecular events that are associated with antibiotic lethality, revealing cytoplasmic condensation as a phenotypic feature of antibiotic-induced bacterial cell death.


Assuntos
Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Citoplasma/metabolismo , Escherichia coli/citologia , Escherichia coli/metabolismo , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana/métodos , Viabilidade Microbiana/efeitos dos fármacos , Microscopia de Força Atômica/métodos , Microscopia de Fluorescência/métodos , Análise de Célula Única/métodos
10.
Aging Cell ; 19(10): e13214, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32898317

RESUMO

The dauer larva of Caenorhabditis elegans, destined to survive long periods of food scarcity and harsh environment, does not feed and has a very limited exchange of matter with the exterior. It was assumed that the survival time is determined by internal energy stores. Here, we show that ethanol can provide a potentially unlimited energy source for dauers by inducing a controlled metabolic shift that allows it to be metabolized into carbohydrates, amino acids, and lipids. Dauer larvae provided with ethanol survive much longer and have greater desiccation tolerance. On the cellular level, ethanol prevents the deterioration of mitochondria caused by energy depletion. By modeling the metabolism of dauers of wild-type and mutant strains with and without ethanol, we suggest that the mitochondrial health and survival of an organism provided with an unlimited source of carbon depends on the balance between energy production and toxic product(s) of lipid metabolism.


Assuntos
Caenorhabditis elegans/metabolismo , Etanol/metabolismo , Animais , Dessecação/métodos , Larva , Metabolismo dos Lipídeos
11.
Sci Rep ; 8(1): 6398, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686301

RESUMO

Proper cholesterol transport is crucial for the functionality of cells. In C. elegans, certain cholesterol derivatives called dafachronic acids (DAs) govern the entry into diapause. In their absence, worms form a developmentally arrested dauer larva. Thus, cholesterol transport to appropriate places for DA biosynthesis warrants the reproductive growth. Recently, we discovered a novel class of glycosphingolipids, PEGCs, required for cholesterol mobilization/transport from internal storage pools. Here, we identify other components involved in this process. We found that strains lacking polyunsaturated fatty acids (PUFAs) undergo increased dauer arrest when grown without cholesterol. This correlates with the depletion of the PUFA-derived endocannabinoids 2-arachidonoyl glycerol and anandamide. Feeding of these endocannabinoids inhibits dauer formation caused by PUFAs deficiency or impaired cholesterol trafficking (e.g. in Niemann-Pick C1 or DAF-7/TGF-ß mutants). Moreover, in parallel to PEGCs, endocannabinoids abolish the arrest induced by cholesterol depletion. These findings reveal an unsuspected function of endocannabinoids in cholesterol trafficking regulation.


Assuntos
Caenorhabditis elegans/metabolismo , Colesterol/metabolismo , Endocanabinoides/metabolismo , Homeostase , Animais , Ácido Araquidônico/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Ácidos Graxos Insaturados/metabolismo , Larva/metabolismo , Mutação
12.
PLoS One ; 11(12): e0167208, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27907064

RESUMO

The free-living soil nematode Caenorhabditis elegans adapts its development to the availability of food. When food is scarce and population density is high, worms enter a developmentally arrested non-feeding diapause stage specialized for long-term survival called the dauer larva. When food becomes available, they exit from the dauer stage, resume growth and reproduction. It has been postulated that compound(s) present in food, referred to as the "food signal", promote exit from the dauer stage. In this study, we have identified NAD+ as a component of bacterial extract that promotes dauer exit. NAD+, when dissolved in alkaline medium, causes opening of the mouth and ingestion of food. We also show that to initiate exit from the dauer stage in response to NAD+ worms require production of serotonin. Thus, C. elegans can use redox cofactors produced by dietary organisms to sense food.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Caenorhabditis elegans/fisiologia , Estágios do Ciclo de Vida , NAD/metabolismo , Animais , NADP/metabolismo , Serotonina/metabolismo
14.
Nat Commun ; 6: 8060, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26290173

RESUMO

Under adverse conditions, Caenorhabditis elegans enters a diapause stage called the dauer larva. External cues signal the nuclear hormone receptor DAF-12, the activity of which is regulated by its ligands: dafachronic acids (DAs). DAs are synthesized from cholesterol, with the last synthesis step requiring NADPH, and their absence stimulates dauer formation. Here we show that NADPH levels determine dauer formation in a regulatory mechanism involving key carbohydrate and redox metabolic enzymes. Elevated trehalose biosynthesis diverts glucose-6-phosphate from the pentose phosphate pathway, which is the major source of cellular NADPH. This enhances dauer formation due to the decrease in the DA level. Moreover, DAF-12, in cooperation with DAF-16/FoxO, induces negative feedback of DA synthesis via activation of the trehalose-producing enzymes TPS-1/2 and inhibition of the NADPH-producing enzyme IDH-1. Thus, the dauer developmental decision is controlled by integration of the metabolic flux of carbohydrates and cellular redox potential.


Assuntos
Caenorhabditis elegans/fisiologia , Animais , Proteínas de Caenorhabditis elegans , Metabolismo dos Carboidratos , Regulação da Expressão Gênica no Desenvolvimento , Larva/fisiologia , Mutação , NADP/metabolismo , Oxirredução , Interferência de RNA , Trealose/biossíntese
15.
Worm ; 1(1): 61-5, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24058825

RESUMO

While life requires water, many organisms, known as anhydrobiotes, can survive in the absence of water for extended periods of time. Although discovered 300 years ago, we know very little about the fascinating phenomenon of anhydrobiosis. In this paper, we summarize our previous findings on the desiccation tolerance of the Caenorhabditis elegans dauer larva. A special emphasis is given to the role of trehalose in protecting membranes against desiccation. We also propose a simple mechanism for this process.

16.
Curr Biol ; 21(15): 1331-6, 2011 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-21782434

RESUMO

Water is essential for life on Earth. In its absence, however, some organisms can interrupt their life cycle and temporarily enter an ametabolic state, known as anhydrobiosis [1]. It is assumed that sugars (in particular trehalose) are instrumental for survival under anhydrobiotic conditions [2]. However, the role of trehalose remained obscure because the corresponding evidence was purely correlative and based mostly on in vitro studies without any genetic manipulations of trehalose metabolism. In this study, we used C. elegans as a genetic model to investigate molecular mechanisms of anhydrobiosis. We show that the C. elegans dauer larva is a true anhydrobiote: under defined conditions it can survive even after losing 98% of its body water. This ability is correlated with a several fold increase in the amount of trehalose. Mutants unable to synthesize trehalose cannot survive even mild dehydration. Light and electron microscopy indicate that one of the major functions of trehalose is the preservation of membrane organization. Fourier-transform infrared spectroscopy of whole worms suggests that this is achieved by preserving homogeneous and compact packing of lipid acyl chains. By means of infrared spectroscopy, we can now distinguish a "dry, yet alive" larva from a "dry and dead" one.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Dessecação , Larva/efeitos dos fármacos , Trealose/farmacologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Modelos Genéticos
17.
Mech Dev ; 126(5-6): 382-93, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19368796

RESUMO

The role of lipids in the process of embryonic development of Caenorhabditis elegans is still poorly understood. Cytochrome P450s, a class of lipid-modifying enzymes, are good candidates to be involved in the production or degradation of lipids essential for development. We investigated two highly similar cytochrome P450s in C. elegans, cyp-31A2 and cyp-31A3, that are homologs of the gene responsible for Bietti crystalline corneoretinal dystrophy in humans. Depletion of both cytochromes either by RNAi or using a double deletion mutant, led to the failure of establishing the correct polarity of the embryo and to complete the extrusion of the polar bodies during meiosis. In addition, the egg became osmotic sensitive and permeable to dyes. The phenotype of cyp-31A2 or cyp-31A3 is very similar to a class of mutants that have polarization and osmotic defects (POD), thus the genes were renamed to pod-7 and pod-8, respectively. Electron microscopic analysis demonstrated that the activity of pod-7/pod-8 is crucial for the proper assembly of the eggshell and, in particular, for the production of its lipid-rich layer. Using a complementation with lipid extracts, we show that POD-7/POD-8 function together with a NADPH cytochrome P450 reductase, coded by emb-8, and are involved in the production of lipid(s) required for eggshell formation.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/enzimologia , Polaridade Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Embrião não Mamífero/citologia , Embrião não Mamífero/enzimologia , Meiose , Óvulo/citologia , Animais , Caenorhabditis elegans/citologia , Proteínas de Caenorhabditis elegans/genética , Divisão Celular , Extratos Celulares , Corantes , Sistema Enzimático do Citocromo P-450/genética , Embrião não Mamífero/ultraestrutura , Lipídeos/química , Redes e Vias Metabólicas , Osmose , Óvulo/enzimologia , Óvulo/ultraestrutura , Permeabilidade , Fenótipo , Interferência de RNA , Deleção de Sequência , Fatores de Tempo
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